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J. Biol. Chem., Vol. 275, Issue 44, 34025-34027, November 3, 2000

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ACCELERATED PUBLICATION
Glutamate Is Not a Messenger in Insulin Secretion^*

Michael J. MacDonald^§ and Leonard A. Fahien^¶

From the  Childrens Diabetes Center and ^¶ Department of Pharmacology, University of Wisconsin Medical School, Madison, Wisconsin 53706

Received for publication, June 27, 2000, and in revised form, August 4, 2000

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Experiments do not support a recent claim that glutamate formed from the amination of citric acid cycle-derived -ketoglutarate is a messenger in glucose-induced insulin secretion (Maechler, P., and Wollheim, C. (1999) Nature 402, 685-689). Glucose, leucine, succinic acid methyl ester, and -ketoisocaproic acid all markedly stimulate insulin release but do not increase glutamate levels in pancreatic islets. Increasing the intracellular glutamate levels to 10-fold higher than basal levels by adding glutamine to islets does not stimulate insulin release. When leucine, in addition to glutamine, is applied to islets, insulin release is almost as high as with glucose alone. This is consistent with the known ability of leucine to allosterically activate glutamate deamination by glutamate dehydrogenase, which can supply -ketoglutarate to the citric acid cycle. Experiments with mitochondria from pancreatic islets suggest that flux through the glutamate dehydrogenase reaction is quiescent during glucose-induced insulin secretion. These experiments support the traditional idea that when insulin release is associated with flux through glutamate dehydrogenase, the flux is in the direction of -ketoglutarate.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Recently Maechler and Wollheim (1), on the basis of intricate and broad-based experiments, proposed that glutamate generated from citric acid cycle-derived -ketoglutarate is a messenger in glucose-induced insulin secretion. The glutamate effect was not robust, and its demonstration seemed to require rather narrowly defined conditions. For example, dimethylglutamate, a glutamate precursor that is permeable to the plasma membrane, caused a leftward shift in the concentration dependence of glucose-stimulated insulin release in INS-1 insulinoma cells. Dimethylglutamate did not stimulate insulin release at a basal concentration of glucose (2.5 mM) or augment insulin release at concentrations of glucose (16.7 to 25 mM) optimal for insulin release. Insulin release by dimethylglutamate was potentiated only at intermediate glucose concentrations. It was reported that when rat insulinoma INS-1 cells were incubated in the presence of a concentration of glucose (12.8 mM) that stimulates insulin release, cellular glutamate levels increased 4.8-fold to a stimulated level of 0.22 mM within 30 min. It was also observed that glucose (16.7 mM) augmented glutamate levels in human pancreatic islets from a basal level of 0.78 to a stimulated level of 3.93 nmol of glutamate per mg of islet protein. However, even these stimulated levels of glutamate are quite low. Our calculations indicate that the basal (0.04 to 0.08 mM) and stimulated glutamate levels (0.2 to 0.4 mM) reported by Maechler and Wollheim (1) are far lower than the basal concentration of glutamate of 1 to 7 mM found in many tissues (2) including the pancreatic islets used in our current study (see below) and in islets studied by others (3, 4).¹ In addition, others have observed previously that glucose does not increase glutamate in islets (3). Thus, even though sophisticated approaches were employed to investigate the glutamate as messenger hypothesis, there was the suggestion from previous reports (3, 4) that the researchers may have inadvertently experienced an artifact in their glutamate estimates (1). Therefore, in the current study we chose to address an issue essential for the support of the major premise of the glutamate as messenger hypothesis. That is, whether increases in intracellular glutamate are associated with insulin release.

Results of simple experiments that permit a straightforward interpretation, unfortunately, cast significant doubt on the idea that glutamate is a messenger for any insulin secretagogue. Glucose and other secretagogues did not increase intracellular glutamate levels in pancreatic islets, and when islet glutamate levels were increased 10-fold by glutamine, insulin release did not occur. Studies with pancreatic islet mitochondria did not suggest that insulin secretagogues increase the amination of -ketoglutarate. The results of the current study support the traditional theory of insulin secretion involving glutamate, which is that leucine, by allosterically activating glutamate dehydrogenase, can stimulate glutamate deamination to -ketoglutarate, which is further metabolized in the citric acid cycle to stimulate insulin secretion (3-9).

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

Pancreatic Islets-- Isolation of islets from pancreata of 250-g Harlan Sprague-Dawley rats and insulin release were performed by standard methods (9, 10). For estimating glutamate production in intact islets, islets (100 per test tube) were incubated in 0.2 ml of Krebs-Ringer bicarbonate buffer, pH 7.3, containing various insulin (non) secretagogues at 37 °C. After 30 min islets were washed for 5 s by adding 1 ml of Krebs-Ringer buffer and centrifuging at 100 × g for 15 s. The islet pellets were immediately homogenized in 50 µl of 6% perchloric acid, and the homogenate was centrifuged at 20,800 × g for 2 min. Supernatant fractions were removed and neutralized to a pH value of ~7 with 30% KOH and centrifuged again to remove potassium perchlorate precipitates.

Mitochondria-- Mitochondria were isolated from pancreatic islets and washed once in MSH (220 mM mannitol, 70 mM sucrose, and 5 mM potassium-Hepes buffer, pH 7.5) or from INS-1 cells and washed twice in MSH as described previously (10). Mitochondria freshly isolated from about 2000 rat pancreatic islets or 0.05 to 0.1 ml of packed INS-1 cells were suspended in 180 µl (240 µl in the case of INS-1 cells) of a solution of MSH containing 2 mM Na₂ADP, 3 mM MgCl₂, 5 mM potassium phosphate, and 5 mM KHCO₃, pH 7.3, and aliquots of 30 µl of the mitochondrial suspension were incubated with various substrates (10). After 30 min the mitochondrial suspensions were centrifuged at 14,000 × g for 2 min, and the supernatant fractions were removed and acidified with 3 µl of 0.92 M perchloric acid. After centrifuging to remove protein, the pH values of resulting supernatant fractions were adjusted to ~7 with ~3 µl of 0.92 M KOH. Potassium perchlorate precipitates were removed by centrifugation.

Metabolite Measurements-- Glutamate and -ketoglutarate were measured by alkali-enhanced fluorescence (10, 11). To measure glutamate 5 µl of neutralized extract (diluted extract was used when the glutamate concentration was very high) was incubated in 25 µl of a reaction mixture of 100 µM NAD, 50 µM Na₂ADP, 7 units/ml of beef liver glutamate dehydrogenase, and 50 mM Bicine² buffer, pH 8.0. After 15 min at room temperature, 25 µl of 200 mM potassium phosphate, pH 11.9, was added, and the mixture was heated at 60 °C for 15 min. Two microliters of 1 M imidazole, pH 8.8, and 50 µl of 12 M NaOH containing 6 mM H₂O₂ were added, and the mixture was heated again at 60 °C for 15 min. -Ketoglutarate in 5 µl of extract was measured in 25 µl of a reaction mixture containing 20 µM NADH, 100 µM Na₂ADP, 25 mM ammonium acetate, and 7 units/ml of glutamate dehydrogenase in 50 mM imidazole buffer, pH 7.0. After 15 min at room temperature, 25 µl of 0.1 M HCl was added, and the mixture was heated at 60 °C for 15 min. Fifty microliters of 12 M NaOH was added, and the mixture was heated again at 60 °C for 15 min. Fluorescence was then measured with an Optical Technology Devices Ratio 2 Fluorometer with a Corning Glass number 5840 filter for excitation and 5030 (half-thickness) and 3389 filters for emission. Fluorescence of replicate reaction mixtures without enzyme was subtracted from total fluorescence to give that due to glutamate or -ketoglutarate and compared with standards of NAD(H), glutamate, and -ketoglutarate (10 to 100 pmol of NAD(H) and 10 pmol to 0.5 nmol of glutamate and -ketoglutarate). Total protein in islet and mitochondrial pellets was measured by the Lowry method (12).

	RESULTS AND DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS AND DISCUSSION REFERENCES

If glutamate is an intracellular messenger in insulin secretion, then increasing the beta cell glutamate levels by almost any means should stimulate insulin release as long as there is a source of energy supplied by a metabolizable secretagogue. We found higher basal levels of glutamate (1 to 2.5 mM)¹ in pancreatic islets than Maechler and Wollheim (1) observed in stimulated insulinoma cells and pancreatic islet cells, and we did not see glutamate levels rise above background levels in the presence of glucose, the most potent physiologic metabolizable insulin secretagogue (Table I). In addition, the metabolizable insulinotropic agents succinic acid methyl ester and -ketoisocaproic acid did not increase cellular glutamate levels. However, we observed that glutamine, which is permeable to the plasma membrane and is known not to be an insulin secretagogue when applied to islets by itself (9), increased cellular glutamate levels up to 10-fold without increasing insulin release. These experiments do not support the idea that intracellular glutamate is an intracellular messenger for any insulin secretagogue.

Available evidence does suggest that glutamate under certain circumstances can undergo deamination and metabolism in the citric acid cycle to stimulate insulin secretion. For example, this could occur when glutamate dehydrogenase is allosterically activated by leucine (4-9). Leucine and its nonmetabolizable analog BCH, which can also activate glutamate dehydrogenase, stimulate insulin secretion by themselves (4, 6-9, 13), and there is a great deal of evidence that this is due to enhancing the rate of metabolism of endogenous glutamate (4-9). Leucine and BCH augment the rate of ¹⁴CO₂ formation from islets labeled with trace amounts of [U-¹⁴C]glutamine (7, 8). The amount of insulin released by leucine alone (Table I) or BCH is usually about one-third of that stimulated by glucose alone (9). Although the addition of glutamine alone to the incubation mixture has no effect on insulin release, when glutamine is added along with leucine, insulin release is increased to levels almost as high as with glucose (see Ref. 9 and Table I). Leucine did not increase but lowered the level of glutamate derived from glutamine from 10-fold higher than the basal level to 6-fold higher than the unstimulated level (Table I). This may have been due to its augmenting the metabolism of glutamate (4-9) and/or inhibiting the conversion of glutamine to glutamate (4).

It was hypothesized that glutamate formed in the glutamate dehydrogenase reaction from the amination of -ketoglutarate triggers insulin release by entering insulin secretory granules (1). However, much published evidence (4-9, 13) and evidence presented below suggest that when insulin release is associated with flux through glutamate dehydrogenase, flux is in the direction of -ketoglutarate and not in the direction of glutamate. Glucose stimulates insulin release by aerobic glycolysis. It is known that the beta cell possesses pyruvate carboxylase and that one-half of glucose-derived pyruvate enters the citric acid cycle via carboxylation, which can augment cycle intermediates by anaplerosis (10, 14-17). Surplus intermediates are exported from the mitochondria (10). Data from experiments with isolated mitochondria from islets or INS-1 cells (Table II) agreed with the studies with intact islets. When pyruvate, the final product of glycolysis, was added to pancreatic islet mitochondria or INS-1 cell mitochondria (a situation analogous to adding glucose to intact beta cells), glutamate export was not augmented, but export of -ketoglutarate was increased slightly (3-fold). Succinate increases the export of several metabolites, such as malate, 20- to 50-fold (data not shown), but adding succinate (a situation similar to adding the secretagogue methyl succinate to intact islets) did not increase the export of glutamate or -ketoglutarate. When -ketoglutarate was added alone, glutamate export was not increased. However, when glutamate was added, -ketoglutarate export increased only slightly (2-fold) unless pyruvate was also added to transaminate with glutamate. Similarly, it was only when aspartate, which via transamination can contribute an amino group to -ketoglutarate to form glutamate, was added along with -ketoglutarate or with pyruvate that glutamate export increased significantly (Table II). When pyruvate and aspartate were added together, both glutamate and -ketoglutarate export were increased. The increase in glutamate export could result from transamination of aspartate catalyzed by aspartate aminotransferase, whereas the increase in -ketoglutarate could be because pyruvate increased the level of -ketoglutarate through anaplerosis (10, 16). Thus, because there was only significant export of glutamate from islet mitochondria when aspartate was added with either -ketoglutarate or pyruvate, and because pyruvate, succinate, and -ketoglutarate failed to promote significant export of glutamate, it seems unlikely that glutamate generated in beta cell mitochondria could be an intracellular messenger in glucose-induced insulin secretion. Glutamate can, however, become a metabolizable insulin secretagogue when its deamination is activated by leucine (4-9).

View this table: [in this window] [in a new window]   Table II Export of glutamate and -ketoglutarate from rat pancreatic islet or INS-1 mitochondria supplied with various substrates All substrate concentrations were 5 mM. Results with islets are the mean ± S.E., and the number of replicate incubations are in parentheses. Results with INS-1 cells show duplicate measurements. NM indicates not measured.

The idea that glutamate deamination catalyzed by glutamate dehydrogenase is a mechanism of insulin secretion in humans is suggested by the hypoglycemic disease hyperinsulinism/hyperammonemia syndrome. This disease is caused by various gain of function mutations in the glutamate dehydrogenase gene in exons encoding the binding site for GTP (18), an allosteric inhibitor of the enzyme (19, 20). Because this results in the enzyme having a lower affinity for GTP, glutamate deamination catalyzed by the enzyme should be always activated. In the beta cell where the level of glutamate dehydrogenase is low, this would result in persistently enhanced insulin secretion and increased generation of ammonia by glutamate dehydrogenase. Excessive liver glutamate dehydrogenase activity may also explain the hyperammonemia (18).³

It is interesting that not only is it unlikely that glutamate is involved in glucose-induced insulin secretion but also that the activation processes of glucose-induced insulin release and glutamate metabolism-induced insulin release appear to be reciprocal to one another. Pancreatic islets maintained in a normal or a high concentration of glucose exhibit an intact response to glucose but markedly decreased insulin release in response to leucine, whereas islets maintained in a low concentration of glucose show a normal or enhanced leucine response (13, 21, 22) and markedly diminished glucose response (21, 22). The low glucose effect may explain beta cell hypersensitivity to leucine frequently seen in hypoglycemic states (13). The mechanism of the suppression by glucose of leucine-induced insulin release has been suggested to be due to inhibition of glutamate deamination from increased levels of GTP and altered levels of other effectors of glutamate dehydrogenase resulting from glucose metabolism (13).

	ACKNOWLEDGEMENTS

We thank Heather Drought and Richard C. Raphael for technical assistance.

	FOOTNOTES

^* This study was supported by National Institutes of Health Grant DK28348, the Oscar C. Rennebohm Foundation, and the Robert Wood Johnson Family Trust.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ To whom correspondence should be addressed: Rm. 3459 Medical Science Center, 1300 University Ave., Madison, WI 53706. Tel.: 608-262-1195; Fax: 608-262-9300; E-mail: mjmacdon@facstaff.wisc.edu.

Published, JBC Papers in Press, August 30, 2000, DOI 10.1074/jbc.C000411200

¹ Calculations with data from Ref. 1 and Table 1 were made assuming that islets contain 50 to 130 mg of protein/gm wet weight of tissue, that the water content of islets is 3.2 liters of water/kg dry weight (23) with data from Refs. 3 and 4, and that the average dry weight of one islet is 1.3 µg (24) with data from Ref. 4.

³ It is difficult to explain the hyperammonemia solely on the basis of an increase in liver glutamate dehydrogenase activity. This is because in liver mitochondria the level of glutamate dehydrogenase active sites is very high (25) such that the glutamate dehydrogenase reaction is at equilibrium (26). Consequently, decreased binding of GTP should not alter the net rate of flux through glutamate dehydrogenase. This may indicate that there are other metabolic alterations secondary to the mutation in this enzyme that play a role in the hyperammonemia.

	ABBREVIATIONS

The abbreviations used are: Bicine, N,N-bis(2-hydroxyethyl)glycine; BCH, 2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid..

	REFERENCES

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